Discovery of the Selective and Orally Available Galectin-1 Inhibitor GB1908 as a Potential Treatment for Lung Cancer
(2024) In Journal of Medicinal Chemistry- Abstract
- We have previously described a new series of selective and orally
available galectin-1 inhibitors resulting in the thiazole-containing
glycomimetic GB1490. Here, we show that the introduction of polar
substituents to the thiazole ring results in galectin-1-specific
compounds with low nM affinities. X-ray structural analysis of a new
ligand-galectin-1 complex shows changes in the binding mode and
ligand-protein hydrogen bond interactions compared to the
GB1490-galectin-1 complex. These new high affinity ligands were further
optimized with respect to affinity and ADME properties resulting in the
galectin-1-selective GB1908 (Kd galectin-1/3 0.057/6.0 μM). In vitro GB1908 inhibited... (More) - We have previously described a new series of selective and orally
available galectin-1 inhibitors resulting in the thiazole-containing
glycomimetic GB1490. Here, we show that the introduction of polar
substituents to the thiazole ring results in galectin-1-specific
compounds with low nM affinities. X-ray structural analysis of a new
ligand-galectin-1 complex shows changes in the binding mode and
ligand-protein hydrogen bond interactions compared to the
GB1490-galectin-1 complex. These new high affinity ligands were further
optimized with respect to affinity and ADME properties resulting in the
galectin-1-selective GB1908 (Kd galectin-1/3 0.057/6.0 μM). In vitro GB1908 inhibited galectin-1-induced apoptosis in Jurkat cells (IC50
= 850 nM). Pharmacokinetic experiments in mice revealed that a dose of
30 mg/kg b.i.d. results in free levels of GB1908 in plasma over
galectin-1 Kd for 24 h. GB1908 dosed with this regimen reduced the growth of primary lung tumor LL/2 in a syngeneic mouse model. (Less)
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https://lup.lub.lu.se/record/236045e0-059c-48f5-8942-1091ea1476bd
- author
- organization
- publishing date
- 2024-05-28
- type
- Contribution to journal
- publication status
- epub
- subject
- in
- Journal of Medicinal Chemistry
- publisher
- The American Chemical Society (ACS)
- external identifiers
-
- scopus:85194404639
- pmid:38804039
- ISSN
- 1520-4804
- DOI
- 10.1021/acs.jmedchem.4c00485
- language
- English
- LU publication?
- yes
- id
- 236045e0-059c-48f5-8942-1091ea1476bd
- date added to LUP
- 2024-05-30 17:22:16
- date last changed
- 2024-06-24 12:43:43
@article{236045e0-059c-48f5-8942-1091ea1476bd, abstract = {{We have previously described a new series of selective and orally <br> available galectin-1 inhibitors resulting in the thiazole-containing <br> glycomimetic GB1490. Here, we show that the introduction of polar <br> substituents to the thiazole ring results in galectin-1-specific <br> compounds with low nM affinities. X-ray structural analysis of a new <br> ligand-galectin-1 complex shows changes in the binding mode and <br> ligand-protein hydrogen bond interactions compared to the <br> GB1490-galectin-1 complex. These new high affinity ligands were further <br> optimized with respect to affinity and ADME properties resulting in the <br> galectin-1-selective GB1908 (<i>K</i><sub>d</sub> galectin-1/3 0.057/6.0 μM). In vitro GB1908 inhibited galectin-1-induced apoptosis in Jurkat cells (IC<sub>50</sub><br> = 850 nM). Pharmacokinetic experiments in mice revealed that a dose of <br> 30 mg/kg b.i.d. results in free levels of GB1908 in plasma over <br> galectin-1 <i>K</i><sub>d</sub> for 24 h. GB1908 dosed with this regimen reduced the growth of primary lung tumor LL/2 in a syngeneic mouse model.}}, author = {{Zetterberg, Fredrik R. and Peterson, Kristoffer and Nilsson, Ulf J. and Andréasson Dahlgren, Kajsa and Diehl, Carl and Hoyler, Ian and Håkansson, Maria and Khabut, Areej and Kahl-Knutson, Barbro and Leffler, Hakon and MacKinnon, Alison C. and Roper, James A. and Slack, Robert J. and Zarrizi, Reihaneh and Pedersen, Anders}}, issn = {{1520-4804}}, language = {{eng}}, month = {{05}}, publisher = {{The American Chemical Society (ACS)}}, series = {{Journal of Medicinal Chemistry}}, title = {{Discovery of the Selective and Orally Available Galectin-1 Inhibitor GB1908 as a Potential Treatment for Lung Cancer}}, url = {{http://dx.doi.org/10.1021/acs.jmedchem.4c00485}}, doi = {{10.1021/acs.jmedchem.4c00485}}, year = {{2024}}, }